Abstract for Project 1 (Chen) Recognition and elimination of foreign DNA is a fundamental mechanism of host defense. Cytosolic DNA is a danger signal that triggers intrinsic immunity pathways. cGAS is a DNA sensing enzyme that produces cyclic GMP-AMP (cGAMP), which functions as a second messenger that binds to and activates the adaptor protein STING to induce type-I interferons and other cytokines. The cGAS-STING pathway has emerged as a major innate immunity pathway that detects cancer cells and launches anti-tumor immune responses. Indeed, the delivery of cGAMP and its analogues to tumor-bearing mice activates tumor immunity that retards tumor growth and prolongs animal survival. However, major hurdles exist before cGAMP-based therapies can benefit human cancer patients. One hurdle is that systemic delivery of cGAMP may lead to immunotoxicity associated with ?cytokine storm?. At the basic science level, the mechanism by which the cGAS-STING pathway activates anti-tumor immune responses is still poorly understood. In this application, we propose to investigate the mechanism underlying cGAS activation in tumors and develop tumor-targeting strategies to improve the efficacy and safety of cGAMP-based therapies. We will carry out the following three specific Aims: (1) Investigate the role of the cGAS-STING pathway in anti-tumor immunity; (2) Improve the efficacy and safety of cGAMP-based therapies through nanoparticles and combination with tumor-targeting cytokines; and (3) Investigate the role of the cGAS- STING pathway in endogenous tumors. We anticipate this project will generate fundamental insights in intrinsic tumor immunity and also through collaborations with Dr. Gao and Dr. Fu to harness the body?s innate and adaptive immune system to improve cancer immunotherapies.